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Genetic counseling: Gaucher Disease
Gaucher Disease General facts *most common lysosomal storage disease *most common genetic disorder among Ashkenazi Jews *less than 1/40,000 in gen pop affected *autosomal recessive inheritance *deficient activity of beta-glucocerebrosidase *enzyme needed to break down glucocerebroside (lipid result of breakdown of worn out RBC and WBC) *lack of causes accumulation in lysosomes of macrophages (which are responsible for recycling and breaking it down) *accumulation of these cells primarily in liver, spleen, and bone marrow (sometimes lungs) 3 types of Gaucher Disease *type 1 - nonneuronopathic, most common type (99% of patients) *type 2 - infantile type (early onset and severe CNS involvement and death early childhood) *type 3 - onset of mild CNS in adolescence or early adult Symptoms of type 1 *variable extent of involvement and symptoms even in siblings with same mutation *generally later in life symptoms appear less likely severe disease *enlarged liver and spleen (hepatosplenomegaly) most common sign *anemia and thromocytopenia secondary to enlarged spleen and accumulation in bone marrow *skeletal involvement in 70-100% includes: osteopenia, lytic lesions, chronic bone pain, acute episodes of "bone crisis", bone infarcts, osteonecrosis, subchondral joint collapse w/ secondary degenerative arthritis, (femur, vertebrae, humerus, tibia most dramatically affected) *more than half have erlenmeyer flask deformity of femur *bone problems cause greatest morbidity and long-term disability Diagnosis *most efficient and reliable is assay of enzyme activity (blood leukocytes or can use skin fibroblasts) *individual with adult Gaucher will have 10-30% of normal values *heterozygotes have reduced levels, but range overlaps normal population so not good for carrier testing *bone marrow biopsy may provide suspicion due to lipid-laden macrophages, but enzyme tests must confirm because can look similar to other cells in other diseases (see differential) *prenatal dx available amnio or CVS gene testing *gene maps to 1q2.1 *more than 150 mutations identified *carrier freq. in AJ pop is 1 in 14 to 1 in 18 (4 mutations, N370S, 84GG, L444P, IVS2+1, account for >90% in symptomatic patients) *non-Jewish - much lower carrier frequ and L44P, N370S, D409H, R463c, and IVS2 +1 most common *mutation testing can determine carrier status *detects about 84% of all carriers and 90% of AJ carriers *tests most common alleles (N37OS most common AJ pop, L444P most common world wide, 1Vs2, 84GG, V394L *gene sequencing on research basis genotype phenotype correlation *homozygous N370S associated with less severe phenotype and no CNS involvement (some homozygotes in AJ pop. may be asymptomatic and not come to medical attention) *homozygous L444P early CNS symptoms common in type 2 and 3 Treatment *traditionally was periodic blood transfusions, partial or total spleen removal, pain relievers *regular evaluations to monitor rate of progression *type 1 and some type 3 responds to ERT with purified macrophage-targeted human beta-glucocerebrosidase (aglucerase injection) *ERT reduces liver and spleen size, decreased bone pain, resolves anemia and thrombocytopenia *does not seem to correct osteonecrosis, osteosclerosis, vertebral compression *IgG antibodies to aglucerase reported in 13% of patients (usually with no clinical effect and diminish with continued therapy) *But antibodies associated with increased risk of hypersensitivity reactions *high cost of ERT $100 per pound of weight every 2 wks Differential Diagnosis *Pseudo-Gaucher cells-seen in chronic granulocytic leukemia, thalassemia, multiple myeloma, Hodgkin Disease, lymphomas, acute lymphocytic leukemia *Organomegaly - seen in Nieman-Pick type A,B,C, Wolman Disease, mucopolysaccharidoses, oligosaccharidoses *Other lysomal storage diseases Psychosocial Considerations *stress of living with chronic illness *difficulty accepting that we may not know if some of the symptoms really are related to Gaucher *difficulty accepting the metabolic changes that are often occur once on ERT *possible lifestyle limitations due to arthritis and pain *many don't appear sick, so may not have support from others *uncertainties about symptom severity and onset *coping with pain and fatigue *how supportive are family and friends *is she involved with a support group *insurance and financial issues Resources *National Gaucher Foundation (NGF) :11140 Rockville Pike, Suite 350 :Rockville, MD 20852-3106 :ngf@gaucherdisease.org :http://www.gaucherdisease.org :Tel: 301-816-1515 or 1-800-925-8885 :Fax: 301-816-1516 :--grants financial assistance to patients who can't afford insurance premiums :--international symposiums (patients welcome) :--publishes newsletter *Genzyme's Patient Assistance program (helps provide reimbursement and deal with financial concerns) :1-800-745-4447 *Gaucher Registry www.gaucherregistry.com (collects patient data to help understand disease and treatment better) References *Archives of Internal Medicine. Gaucher Disease: Recommendations on diagnosis, Evaluation, and Monitoring. Charrow, J. et al. Published by AMA Sept 1998. *Geneclinics GeneReviews. Gaucher Disease. July 2000. *Cerazyme patient information packet. Genzyme Therapeutics. Notes The information in this outline was last updated in 2002. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.